Although C-reactive protein (CRP) has been shown to have a strong predictive value for future cardiovascular disease (CVD), it is still unclear whether CRP is a non-specific risk marker or a direct mediator in the pathogenesis of CVD. Despite the great clinical importance of CRP, we currently lack an appropriate animal model to study its role in CVD since mouse is not an appropriate animal model to study CRP functions. In this revised application, we have successfully generated both liver-specific (systemic) and vascular-specific (local) CRP transgenic rabbits because rabbits have a cardiovascular system and CRP response that are similar to those of humans. Intriguingly, our preliminary data have documented for the first time that increased systemic CRP can promote atherosclerosis in liver-specific CRP transgenic rabbits. Thus, the availability of these two unique CRP transgenic rabbit models would provide us powerful tools to define whether CRP participates in pathogenesis of CVD. In this proposal, we will test the central hypothesis that both liver-derived CRP and vascular-derived CRP act synergistically to produce the most extensive vascular lesion formation by activating vascular smooth muscle cell proliferation and migration in response to vascular injury. Specifically, we will 1). Define that CRP participates in pathogenesis of vascular disease using novel transgenic rabbit models, and 2). Define the relative influence of systemic CRP versus local CRP as a "vasculopathic" mediator of vascular lesion formation in vivo. Overall, these studies will provide a definitive characterization of the mediator influence of CRP in CVD. Our studies will have profound implications on the understanding of CRP function in vascular disease and the full utility of CRP as a biomarker that guides clinical risk assessments and therapeutic strategies to prevent and treat CVD. PUBLIC HEALTH RELEVANCE: C-reactive protein (CRP) is an acute-phase reactant that exhibits increases in plasma levels during infection, systematic inflammation and tissue injury. Recently, epidemiological studies have demonstrated that circulating CRP levels are associated with an increased risk of cardiovascular disease (CVD) among apparently healthy individuals. Although CRP has been shown to have a strong predictive value for future CVD, it is still unclear whether CRP is a non- specific risk marker or a direct mediator in the pathogenesis of CVD. The studies proposed in this application will provide a definitive characterization of the mediator influence of CRP in CVD using CRP transgenic rabbit models. Our studies will have profound implications on the understanding of CRP biology in vascular diseases.